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BETA
Andersen, Peter
Alternative names
Publications (10 of 127) Show all publications
Fogh, I., Lin, K., Tiloca, C., Rooney, J., Gellera, C., Diekstra, F. P., . . . Powell, J. (2016). Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis. JAMA Neurology, 73(7), 812-820.
Open this publication in new window or tab >>Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis
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2016 (English)In: JAMA Neurology, ISSN 2168-6149, E-ISSN 2168-6157, Vol. 73, no 7, 812-820 p.Article in journal (Refereed) Published
Abstract [en]

IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset. OBJECTIVE To identify gene variants influencing survival in ALS. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed bymeta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis. RESULTS Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 x 10(-9)) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 x 10(-8)). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 x 10(-9)), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 x 10(-8)), corresponding to a 4-month reduction in survival compared with TT carriers. CONCLUSIONS AND RELEVANCE This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.

Keyword
Motor-neuron disease, ALS, C9ORF72, Genome-wide association
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-124512 (URN)10.1001/jamaneurol.2016.1114 (DOI)000379420500013 ()27244217 (PubMedID)
Available from: 2016-08-19 Created: 2016-08-15 Last updated: 2017-05-10Bibliographically approved
Brenner, D., Andersen, P. M., Ludolph, A. C. & Weishaupt, J. H. (2016). Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice" [Letter to the editor]. Journal of Immunology, 196(2), 530.
Open this publication in new window or tab >>Comment on "Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice"
2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 2, 530- p.Article in journal, Letter (Refereed) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-116077 (URN)10.4049/jimmunol.1502255 (DOI)000368072100006 ()26747568 (PubMedID)
Available from: 2016-02-10 Created: 2016-02-08 Last updated: 2018-01-10Bibliographically approved
Keskin, I., Forsgren, E., Lange, D. J., Weber, M., Birve, A., Synofzik, M., . . . Marklund, S. L. (2016). Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients. PLoS ONE, 11(2), Article ID e0150133.
Open this publication in new window or tab >>Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, e0150133Article in journal (Refereed) Published
Abstract [en]

Mutations in superoxide dismutase-1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.

Keyword
Superoxides, Amyotrophic Lateral Sclerosis
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-118791 (URN)10.1371/journal.pone.0150133 (DOI)000371274400090 ()26919046 (PubMedID)
Available from: 2016-04-08 Created: 2016-04-04 Last updated: 2018-01-10Bibliographically approved
Menke, R. A. L., Proudfoot, M., Wuu, J., Andersen, P. M., Talbot, K., Benatar, M. & Turner, M. R. (2016). Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk. Journal of Neurology, Neurosurgery and Psychiatry, 87(6), 580-588.
Open this publication in new window or tab >>Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk
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2016 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 87, no 6, 580-588 p.Article in journal (Refereed) Published
Abstract [en]

Objective To discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS).

Methods T1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3 T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed.

Results Grey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls.

Conclusions Rather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies.

National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-122555 (URN)10.1136/jnnp-2015-311945 (DOI)000376686100003 ()26733601 (PubMedID)
Available from: 2016-07-26 Created: 2016-06-20 Last updated: 2017-05-11Bibliographically approved
Tokuda, E., Brännström, T., Andersen, P. M. & Marklund, S. L. (2016). Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase. Acta neuropathologica communications, 4, Article ID 6.
Open this publication in new window or tab >>Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase
2016 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 4, 6Article in journal (Refereed) Published
Abstract [en]

Introduction: The motor system is selectively vulnerable to mutations in the ubiquitously expressed aggregation-prone enzyme superoxide dismutase-1 (SOD1).

Results: Autophagy clears aggregates, and factors involved in the process were analyzed in multiple areas of the CNS from human control subjects (n = 10) and amyotrophic lateral sclerosis (ALS) patients (n = 18) with or without SOD1 mutations. In control subjects, the key regulatory protein Beclin 1 and downstream factors were remarkably scarce in spinal motor areas. In ALS patients, there was evidence of moderate autophagy activation and also dysregulation. These changes were largest in SOD1 mutation carriers. To explore consequences of low autophagy capacity, effects of a heterozygous deletion of Beclin 1 were examined in ALS mouse models expressing mutant SOD1s. This caused earlier SOD1 aggregation, onset of symptoms, motor neuron loss, and a markedly shortened survival. In contrast, the levels of soluble misfolded SOD1 species were reduced.

Conclusions: The findings suggest that an inherent low autophagy capacity might cause the vulnerability of the motor system, and that SOD1 aggregation plays a crucial role in the pathogenesis.

Keyword
Amyotrophic lateral sclerosis, Autophagy, Motor system vulnerability, Protein aggregates, Superoxide sumutase-1
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-116740 (URN)10.1186/s40478-016-0274-y (DOI)000368653000001 ()26810478 (PubMedID)
Available from: 2016-02-19 Created: 2016-02-11 Last updated: 2018-01-10Bibliographically approved
Wuolikainen, A., Jonsson, P., Ahnlund, M., Antti, H., Marklund, S. L., Moritz, T., . . . Trupp, M. (2016). Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects. Molecular Biosystems, 12(4), 1287-1298.
Open this publication in new window or tab >>Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects
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2016 (English)In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 12, no 4, 1287-1298 p.Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are protein-aggregation diseases that lack clear molecular etiologies. Biomarkers could aid in diagnosis, prognosis, planning of care, drug target identification and stratification of patients into clinical trials. We sought to characterize shared and unique metabolite perturbations between ALS and PD and matched controls selected from patients with other diagnoses, including differential diagnoses to ALS or PD that visited our clinic for a lumbar puncture. Cerebrospinal fluid (CSF) and plasma from rigorously age-, sex- and sampling-date matched patients were analyzed on multiple platforms using gas chromatography (GC) and liquid chromatography (LC)-mass spectrometry (MS). We applied constrained randomization of run orders and orthogonal partial least squares projection to latent structure-effect projections (OPLS-EP) to capitalize upon the study design. The combined platforms identified 144 CSF and 196 plasma metabolites with diverse molecular properties. Creatine was found to be increased and creatinine decreased in CSF of ALS patients compared to matched controls. Glucose was increased in CSF of ALS patients and alpha-hydroxybutyrate was increased in CSF and plasma of ALS patients compared to matched controls. Leucine, isoleucine and ketoleucine were increased in CSF of both ALS and PD. Together, these studies, in conjunction with earlier studies, suggest alterations in energy utilization pathways and have identified and further validated perturbed metabolites to be used in panels of biomarkers for the diagnosis of ALS and PD.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-119312 (URN)10.1039/c5mb00711a (DOI)000372612600023 ()26883206 (PubMedID)
Available from: 2016-04-17 Created: 2016-04-15 Last updated: 2017-05-11Bibliographically approved
Brenner, D., Mueller, K., Wieland, T., Weydt, P., Boehm, S., Lule, D., . . . Weishaupt, J. H. (2016). NEK1 mutations in familial amyotrophic lateral sclerosis [Letter to the editor]. Brain, 139, CP14-CP17.
Open this publication in new window or tab >>NEK1 mutations in familial amyotrophic lateral sclerosis
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2016 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 139, CP14-CP17 p.Article in journal, Letter (Refereed) Published
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-123374 (URN)10.1093/brain/aww033 (DOI)000376107200001 ()26945885 (PubMedID)
Available from: 2016-07-04 Created: 2016-07-01 Last updated: 2018-01-10Bibliographically approved
Weydt, P., Oeckl, P., Huss, A., Mueller, K., Volk, A. E., Kuhle, J., . . . Otto, M. (2016). Neurofilament Levels as Biomarkers in Asymptomatic and Symptomatic Familial Amyotrophic Lateral Sclerosis. Annals of Neurology, 79(1), 152-158.
Open this publication in new window or tab >>Neurofilament Levels as Biomarkers in Asymptomatic and Symptomatic Familial Amyotrophic Lateral Sclerosis
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2016 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, no 1, 152-158 p.Article in journal (Refereed) Published
Abstract [en]

Neurofilaments are elevated in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients. However, timing of this increase is unknown. To characterize the premanifest disease phase, we performed a cross-sectional study on asymptomatic (n=12) and symptomatic (n=64) ALS mutation carriers and family controls (n=19). Neurofilaments NF-L (neurofilament-light chain) and pNF-H (phosphorylated neurofilament-heavy chain) are normal before symptom onset and increased by at least an order of magnitude at early symptom onset in CSF (pNF-H) or serum and CSF (NF-L). Thus, blood and CSF neurofilament levels are linked to the symptomatic phase of ALS and might serve as objective markers of structural damage to the nervous system.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-118422 (URN)10.1002/ana.24552 (DOI)000370642600016 ()26528863 (PubMedID)
Available from: 2016-04-06 Created: 2016-03-18 Last updated: 2018-01-10Bibliographically approved
Steinacker, P., Feneberg, E., Weishaupt, J., Brettschneider, J., Tumani, H., Andersen, P. M., . . . Otto, M. (2016). Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. Journal of Neurology, Neurosurgery and Psychiatry, 87(1), 12-20.
Open this publication in new window or tab >>Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients
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2016 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 87, no 1, 12-20 p.Article in journal (Refereed) Published
Abstract [en]

Objectives Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics). Methods In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed. Results Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration. Conclusions Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.

Keyword
Motor Neurons, Neurofilament Proteins
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-114011 (URN)10.1136/jnnp-2015-311387 (DOI)000366732700004 ()26296871 (PubMedID)
Available from: 2016-01-25 Created: 2016-01-11 Last updated: 2017-11-30Bibliographically approved
Gallo, V., Vanacore, N., Bueno-de-Mesquita, H. B., Vermeulen, R., Brayne, C., Pearce, N., . . . Vineis, P. (2016). Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study. European Journal of Epidemiology, 31(3), 255-266.
Open this publication in new window or tab >>Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study
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2016 (English)In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 31, no 3, 255-266 p.Article in journal (Refereed) Published
Abstract [en]

Previous case-control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the European Prospective Investigation into Cancer and Nutrition. A total of 472,100 individuals were included in the analysis, yielding 219 ALS deaths. At recruitment, information on PA was collected through standardised questionnaires. Total PA was expressed by the Cambridge Physical Activity Index (CPAI) and analysed in relation to ALS mortality, using Cox hazard models. Interactions with age, sex, and anthropometric measures were assessed. Total PA was weakly inversely associated with ALS mortality with a borderline statistically significant trend across categories (p = 0.042), with those physically active being 33 % less likely to die from ALS compared to those inactive: HR = 0.67 (95 % CI 0.42-1.06). Anthropometric measures, sex, and age did not modify the association with CPAI. The present study shows a slightly decreased-not increased like in case-control studies-risk of dying from ALS in those with high levels of total PA at enrolment. This association does not appear confounded by age, gender, anthropometry, smoking, and education. Ours was the first prospective cohort study on ALS and physical activity.

Keyword
Amyotrophic Lateral Sclerosis, Physical activity, Cohort study, EPIC study, Vigorous physical activity, BMI
National Category
Neurosciences Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-120653 (URN)10.1007/s10654-016-0119-9 (DOI)000373642000005 ()26968841 (PubMedID)
Available from: 2016-08-01 Created: 2016-05-18 Last updated: 2018-01-10Bibliographically approved
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